Dose–Response Analysis of the Tubular and Glomerular Effects of Chronic Exposure to Environmental Cadmium

Abstract

We retrospectively analyzed data on the excretion of cadmium (ECd), β2-microglobulin (Eβ2M) and N-acetyl-β-D-glucosaminidase (ENAG), which were recorded for 734 participants in a study conducted in low- and high-exposure areas of Thailand. Increased Eβ2M and ENAG were used to assess tubular integrity, while a reduction in the estimated glomerular filtration rate (eGFR) was a criterion for glomerular dysfunction. ECd, Eβ2M and ENAG were normalized to creatinine clearance (Ccr) as ECd/Ccr, Eβ2M/Ccr and ENAG/Ccr to correct for interindividual variation in the number of surviving nephrons and to eliminate the variation in the excretion of creatinine (Ecr). For a comparison, these parameters were also normalized to Ecr as ECd/Ecr, Eβ2M/Ecr and ENAG/Ecr. According to the covariance analysis, a Cd-dose-dependent reduction in eGFR was statistically significant only when Ecd was normalized to Ccr as ECd/Ccr (F = 11.2, p < 0.001). There was a 23-fold increase in the risk of eGFR ≤ 60 mL/min/1.73 m2 in those with the highest ECd/Ccr range (p = 0.002). In addition, doubling of ECd/Ccr was associated with lower eGFR (β = −0.300, p < 0.001), and higher ENAG/Ccr (β = 0.455, p < 0.001) and Eβ2M/Ccr (β = 0.540, p < 0.001). In contrast, a covariance analysis showed a non-statistically significant relationship between ECd/Ecr and eGFR (F = 1.08, p = 0.165), while the risk of low eGFR was increased by 6.9-fold only among those with the highest ECd/Ecr range. Doubling of ECd/Ecr was associated with lower eGFR and higher ENAG/Ecr and Eβ2M/Ecr, with the β coefficients being smaller than in the Ccr-normalized dataset. Thus, normalization of Cd excretion to Ccr unravels the adverse effect of Cd on GFR and provides a more accurate evaluation of the severity of the tubulo-glomerular effect of Cd.